PIP5K1C is mainly highly expressed in brain and plays an important role in neural signaling pathway [
12,
13].
Pip5k1c -/- mice caused a 50% reduction in PIP2 in brain, leading to an impairment of its depolarization-dependent synthesis in nerve terminals and synaptic defects [
14].
PIP5K1C has been demonstrated to regulate various cellular processes including receptor-mediated calcium signaling transmission, actin cytoskeleton dynamics, endocytosis and exocytosis [
15]. Additionally,
PIP5K1C plays a crucial role in the maintenance of bone development. It exerts its influence on bone growth and development by regulating the movement of calcium ions in cells and body fluids [
8].
Homozygous or compound heterozygous variants in
PIP5K1C have been known to cause LCCS3 through haploinsufficiency mechanisms. LCCS3 was a very rare and severe disorder. To date, 5 variants were identified in
PIP5K1C. In this study, we revealed a novel variant (c.949_952dup, p.S318Ifs*28) in
PIP5K1C (Fig.
3). The expanded mutation spectrum in
PIP5K1C improves the molecular diagnosis of LCCS3. It was observed that all pathogenic variants in
PIP5K1C were located in the PIPK domain (76-449aa). The variants (c.688_689del, p.G230Qfs*114 and c.727G > A, p.D253N) seem to be mutation hotspots. Certainly, it was necessary to add more clinical cases to further expand mutation spectrum.
Currently, only 7 LCCS3 individuals with detailed clinical information, including the two individuals here, have been described (Table
1). All individuals presented with dyskinesia and multiple joint contractures. Novel phenotypes, bilateral dilated lateral ventricles, were observed in our fetus 2 (II-4), which may be related to the high expression of
PIP5K1C in the brain. However, our fetus 1 (II-2) did not show this feature. It indicates that the
PIP5K1C variant can cause phenotypic variability even within the same family. Furthermore, it has been reported that individuals with LCCS7 or LCCS9 also displayed various brain anomalies, such as cerebral and cerebellar atrophy with almost no white matter, thin corpus callosum, and small basal ganglia and hippocampi [
16,
17]. Whether brain anomaly observed in our fetus 2 is truly part of the spectrum of LCCS3 or is a coincidental finding remains to be further investigated. Although multiple joint contractures have been reported as a feature of LCCS3, the detailed phenotypes have not been displayed [
9]. Here, we presented detailed presentations of multiple joint contractures in our two fetuses, including bilateral talipes equinovarus, stiffness in the limbs, extended knees, flexion contractures of fingers and overlapping fingers. Talipes equinovarus has previously been observed in individuals with LCCS9 and 10 [
18,
19], here our two fetuses also exhibited bilateral talipes equinovarus. Ankylosis of knee joint was observed in individuals with LCCS6, 7 and 9, here our fetus 2 (II-4) showed this feature [
5,
18,
20]. Flexion contractures of fingers were reported in individuals with LCCS7, 9, 10, 11, which was also observed in our two fetuses [
5,
18‐
21]. Our findings profiled the picture of multiple joint contractures in LCCS3. Polyhydramnios was a marked feature of LCCS [
16‐
25]. However, this feature has not yet been observed in individuals with LCCS3, which deserves further investigation.
In conclusion, we described in detail the prenatal clinical features of a Chinese pedigree with LCCS3 caused by biallelic pathogenic variants in PIP5K1C. The identification of the novel variant and novel phenotypes expands the variant spectrum of PIP5K1C and enriches the clinical characteristics of LCCS3, which will be valuable for prenatal diagnosis and genetic counseling.